Several lines of evidence implicate the serotonergic system in the pathophysiology of Asperger's disorder. Specifically, the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) and 5-HT2A antagonists, data from studies of peripheral markers, brain imaging studies of 5-HT synthesis and the results of pharmacological challenges with 5-HT agents converge in suggesting that a deficit in 5-HT transmission might contribute to the symptoms of this illness. However, very little specific information is currently available regarding the brain 5-HT system in patients with Asperger's disorder. Over the last few years, the development of new and highly selective radiotracers has greatly increased the ability to image 5-HT function in the living human brain with Positron Emission Tomography (PET). Combined with progress in scanner resolution and sensitivity, these techniques enable the measurement of parameters of 5-HT function in discrete areas of the living brain. The aim of project II is to quantify the anatomical distribution of two key elements of the 5-HT system that have been implicated in Asperger's disorder: the 5-HT transporter (SERT) and the 5-HT2A receptor. SERT availability will be measured with [11C]DASB and 5-HT2A availability will be measured with [11C]MD L 100907. Both radiotracers are newly developed PET agents with excellent imaging properties. Forty adult subjects with Asperger's disorder and forty controls matched for age, gender, IQ and ethnicity will undergo an MRI scan and two PET scans with [11C]DASB and [11C]MDL 100907, respectively. Subjects will be recruited and evaluated by the Clinical Core of the Center. Following the scans, subjects will be treated with fluoxetine in another study. The hypothesis is that patients with Asperger's disorder will show reduced density of SERT and a compensatory upregulation of 5-HT2A receptors in several areas of the limbic system. Based on results of previous functional brain imaging studies, we anticipate that these changes will be most severe in forebrain cortico-limbic areas. The relationship between regional 5-HT abnormalities and symptom clusters as evaluated by the Clinical Core will be assessed. The results of the imaging studies will also be correlated with the results of a clinical trial with fluoxetine, with the hypothesis that patients who show larger deficits in 5-HT function will be the most likely to benefit from fluoxetine treatment.